The Novel Link between Gene Expression Profiles of Adult T-Cell Leukemia/Lymphoma Patients’ Peripheral Blood Lymphocytes and Ferroptosis Susceptibility

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

1. The investigation of anomaly identification in this paper is mostly based on the GSE10846 dataset. In order to ensure the generalizability of identified genes across various populations of Diffuse Large B-Cell Lymphoma (DLBCL), it is recommended to employ a comprehensive approach by utilising several and diverse datasets during the initial analysis. This approach will help ascertain that the found genes are not specific to a single cohort but can be applicable to different DLBCL populations.

2. The study finds genes of interest; however, it does not conduct biological validation or experimental testing to substantiate the involvement of these genes in DLBCL. In order to substantiate the involvement of discovered genes in the pathophysiology and progression of DLBCL, future research endeavours should incorporate laboratory tests.

3.Although the study identifies genes that are linked to prognosis, it does not go into the potential integration of these genes into clinical practice or existing prognostic models. Conducting an investigation into the potential impact of the identified genes on improving current prognostic models and undertake clinical studies to verify their effectiveness in a real-world context.

4.The investigation identifies multiple genes, yet fails to offer a thorough review of the specific mechanisms by which each gene may influence DLBCL or be employed in therapeutic approaches. Further investigation is warranted to conduct a comprehensive analysis of each identified gene, elucidating its significance in diffuse large B-cell lymphoma (DLBCL) and its potential utility as a therapeutic target or biomarker.

5.This study offers significant insights into the identification of potential prognostic markers in DLBCL through the application of anomaly detection and artificial intelligence. However, it is imperative to conduct additional research that includes biological validation, various datasets, and clinical investigations in order to authenticate and expand upon these findings. Further research should also investigate the therapeutic implications of the identified genes and their possible integration into clinical practive.

6. To what extent were the validation datasets robust, and did they exhibit adequate diversity to substantiate the findings across various patient demographics and illness subtypes?Can the patient characteristics and illness stage of the validation set from Tokai University be considered equivalent to those of the GSE10846 dataset?

Comments on the Quality of English Language

major revisions required in order to accept this article

Author Response

1.I believe Reviewer 1 has posted inaccurate comments on this paper. This is because my paper is related to ATL, and it does not use DLBCL or GSE10846. However, I agree with several points in other comments and have made revisions accordingly.

2.If this is changed to ATL, I agree. However, we have previously elucidated the mechanisms of several anti-ATL agents based on our data. For example, Lenalidomide, which we added to Figure 9, has received approval in Japan based on our data (the paper is currently under review in another journal). Additionally, we have published several papers on Hsp90 inhibitors.

3.We have listed previous related trials for candidate drugs in the supplementary file.

4.It is not DLBCL; it is ATL. Regarding biomarkers, we are currently preparing another paper.

5.It is not DLBCL; it is ATL. As mentioned in point 2, our previous data and the perspective in this paper are not contradictory.

6. GSE10846 and Tokai University are not part of our paper. However, we added a comparison of PTCL, AITL, and the expression pathway of as the same T-cell tumors to enhance the logical coherence of this paper. The results demonstrate the uniqueness of ATL, as shown in Figure 6 and the supplementary materials. Therefore, the candidate therapeutic agents (related to ferroptosis) shown in Table 1 provide a new discussion that should be distinguished from our previous reports and PTCL/AITL.

Reviewer 2 Report

Comments and Suggestions for Authors

In a bioinformatics-dominated paper the authors identified up- and downregulated genes in patients with adult T-cell leukemia and screened for the availability of potentially useful drugs.

Specific Points of Criticism:

(1) The title is very long. A shorter, more concise title might be more appealing to attract readers.

(2)  Abstract:  As many potential readers screen first the abstracts, it would be useful to define some abbreviations also in the Abstract, e.g. ATL, DEG, PPI.

(3)  Most of the figures seem to be unfocused.

(4)  Line 271:  Figure 7 (not Figure 8).

(5)  Line 359:  This line seems to be incomplete.

(6)  Line 427 and elsewhere:  Any list of genes should be arranged alphabetically so it would be easier for the reader to spot a particular gene.

(7)  Discussion:  The Discussion is very long. The authors might consider leaving out the extensive description of the action of the drugs.

(8)  Discussion:  The Discussion could be divided into 2 parts:  (a) Discussion and (b) Conclusions (or Summary) which might also include an Outlook. As the mountain of data is very very complex, a „visual summary“ might be useful.

Comments on the Quality of English Language

see above

Author Response

First of all, I would like to express my gratitude for the very constructive comments from Reviewer-2.

(1) I have simplified the title. Thank you.
(2) This is how it turned out due to the limitation of 200 words. I have included all the words you suggested in the Abbreviation section.
(3) I apologize for any inconvenience. To clarify the significance of the work conducted in BioInformatics, we have included graphs and explanatory text. We also present the solution to this issue in the Discussion section.
(4-6) Thank you for your comments.
(7 & 8) I apologize and express my gratitude for your comments. To clearly define the concept of this paper (exploring novel ATL therapeutic candidates using the Ferroptosis signal), we have added explanations about the uniqueness of ATL through a comparison with PTCL/AITL (Fig. 6), as well as an explanation of the analyzed candidate drugs and previously approved molecular targeted drugs (Fig. 9). Thanks to your comments, we have created Fig. 9, which allows readers to start with the interesting parts of the Discussion. I am truly grateful.